Alcohol intoxication or a history of alcohol abuse has long been associated with an increase in inflammatory cell activation, sepsis, organ failure, ARDS and mortality after surgery, injury or infection. While studies have demonstrated abnormal adaptive and innate immunity as a result of alcohol intoxication, the precise cellular mechanisms whereby alcohol elicits these effects are unclear. The present proposal will take both in vivo and in vitro approaches in order to identify the molecular and cellular events mediated by alcohol intoxication or abuse that contribute to human post-challenge complications. Monocytes contribute significantly to the systemic inflammatory response after injury and patterns of aberrant monocyte activation characterize and sustain chronic inflammation disorders. Our preliminary in vitro data demonstrates that in contrast to ethanol, incubation with it's metabolite acetaldehyde, increases the expression of inflammatory mediators and receptors in monocytes and furthermore, when mice are fed moderate or binge amounts of alcohol, which lead to low and high levels of blood acetaldehyde, there is a decrease or an increase, respectively, in the inflammatory component of vascular injury. Based on our observations and reports in the literature, our central hypothesis is that alcohol intoxication or abuse leads to an increased incidence of infection and mortality following surgical, infectious or injury-mediated challenges, due to it's elevation of blood acetaldehyde levels which intensify challenge-mediated aberrant monocyte activation and the synthesis and release of inflammatory mediators from monocytes, resulting in chronic dysfunction at multiple organ sites. Using a NOG mouse that is humanized by engraftment of hematopoietic stem cells to generate myeloid lineage cells we propose to determine how alcohol or it's metabolite, acetaldehyde, alter the expression of human monocyte inflammatory mediators and receptors and induce aberrant patterns of monocyte subset activation. We will also examine, in vitro, the effects of alcohol and acetaldehyde on the expression of human monocyte inflammatory mediators and receptors and identify specific genes that mediate their effects on aberrant patterns of monocyte subset activation. Taken together, it is anticipated that the proposed experiments will provide novel information about the human specific molecular and cellular events mediated by alcohol intoxication or abuse that contribute to surgical, infectious or injury-mediated challenges in order to develop potential targets for therapeutic modulation which would enhance tissue repair and restoration. PUBLIC HEALTH RELEVANCE: These experiments should provide valuable new information central to our understanding of the effects of alcohol intoxication or abuse on the development of complications in patients after surgery, infection or trauma. Because mortality from surgical, infectious or trauma-related complications is so high following alcohol intoxication or abuse, understanding precisely how alcohol increases this risk is clearly of major significance and clinical importance, and will provide significant new information that should enable the development of potential targets for therapeutic modulation which would enhance tissue repair and restoration.